Cell Envelope Homeostasis in Bacillus subtilis

枯草芽孢杆菌的细胞包膜稳态

• 批准号: 10335184
• 负责人: DAVID Z RUDNER
• 金额: $ 34.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335184
• 关键词: ATP-Binding Cassette Transporters; Address; Antibiotic Therapy; Antibiotics; Area; Bacillus subtilis; Bacteria; Binding; Biochemical; Biogenesis; Cell Wall; Cells; Complement; Complex; Data; Deacetylase; Defect; Development; Ensure; Extracellular Domain; Genes; Genetic Transcription; Gram-Positive Bacteria; Grant; Growth; Homeostasis; Hydrolase; Hydrolysis; Infection; Knowledge; Link; LytA enzyme; Membrane; Membrane Proteins; Modeling; Monitor; Mutation; N-Acetylmuramoyl-L-alanine Amidase; Pathogenesis; Pathway interactions; Peptidoglycan; Play; Polymers; Polysaccharides; Process; Proteolysis; Regulation; Regulatory Pathway; Research; Rod; Role; Sigma Factor; Signal Pathway; Signal Transduction; Stress; Surface; Therapeutic Intervention; Vaccine Therapy; antimicrobial; biological adaptation to stress; cell envelope; cell growth; crosslink; environmental stressor; genetic analysis; novel; response; transcription factor

PROJECT SUMMARY Bacteria are surrounded by a cell envelope that is essential for growth, integrity, and pathogenesis. The envelope and the biogenesis pathways that build it are also the target of many of our most effective antibiotic and vaccine therapies. Because cell envelope biogenesis has been such a successful target, it has been an active area of research for over half a century. Most of the genes responsible for the synthesis and remodeling of the different surface polymers have been identified and their biochemical activities characterized. However, our understanding of how these different assembly pathways are regulated and coordinated with each other during growth remains limited. This proposal focuses on two outstanding questions related to how bacteria coordinate envelope assembly, both principally focused on the cell wall peptidoglycan (PG). Cell growth requires PG synthesis but also the activity of cell wall hydrolases to allow expansion of the PG meshwork. How these potentially lytic enzymes are regulated and coordinated with growth remains an unanswered question in all bacteria. The first two aims of this proposal focus on how the model gram-positive bacterium Bacillus subtilis regulates two functionally redundant cell wall hydrolases and how it coordinates their activities with cell wall synthesis and envelope expansion. The third aim focuses on how cells sense and respond to perturbations to cell wall biogenesis. The σM-signaling pathway was identified over two decades ago as a stress-response pathway that is induced upon environmental stresses, including cell wall targeting antibiotics. This pathway is active at intermediate levels during unperturbed growth and functions in cell envelope homeostasis, monitoring envelope assembly and adjusting flux through the PG biogenesis pathway. What this pathway senses and how it transduces this information across the membrane have remained mysterious. The results of the proposed studies will elucidate critical regulatory pathways in envelope biogenesis and will inform the development of new treatments for infections. The Specific Aims of this application are: Aim 1: Elucidate how cells sense and respond to the extent of PG crosslinking to ensure proper expansion of the cell wall. Aim 2 Investigate how cell wall hydrolysis is coordinated with cell wall synthesis during growth. Aim 3: Determine how cells sense and respond to perturbations to cell envelope biogenesis.

项目摘要 细菌被细胞包膜包围，这对于生长，完整性和发病机理必不可少。这 信封和构建它的生物发生途径也是我们许多最有效抗生素的靶标 和疫苗疗法。因为细胞包膜生物发生一直是一个成功的靶标，所以它一直是 积极的研究领域已有半个多世纪。负责合成和重塑的大多数基因 已经鉴定出不同的表面聚合物，其生化活性的特征是。然而， 我们对这些不同的组装途径如何受到调节和协调的理解 在增长过程中仍然有限。 该提案重点介绍了两个与细菌如何坐标信封组件相关的未悬而未决的问题， 两者主要集中在细胞壁辣椒胶囊（PG）上。细胞生长需要PG合成，但也需要 细胞壁水解的活性以允许PG网状功能扩展。这些潜在的裂解酶是如何 在所有广播中，受监管和协调的增长仍然是一个未解决的问题。前两个目标 该建议的重点是模型革兰氏阳性细菌枯草芽孢杆菌如何调节两个功能 冗余细胞壁水解酶及其如何与细胞壁合成和包膜协调其活动 扩张。第三目的重点是细胞如何感知和对细胞壁生物发生的扰动。这 二十年前将σm信号途径鉴定为一种应力 - 响应途径，该途径被诱导 环境应力，包括靶向抗生素的细胞壁。该途径在中间级别处于活动状态 在细胞包膜内稳态，监测包膜组件和 通过PG生物发生途径调节通量。这条路的感官以及它如何传递 整个膜上的信息仍然神秘。拟议的研究的结果将阐明 包膜生物发生中的关键调节途径，并将为开发新的治疗方法 感染。本应用程序的具体目的是： 目标1：阐明细胞如何感知和响应PG交联的程度，以确保正确扩展 细胞壁。 AIM 2研究细胞壁水解如何与生长过程中的细胞壁合成协调。 目标3：确定细胞如何感知并对细胞包膜生物发生的扰动反应。

项目成果

High-Throughput Imaging of Bacillus subtilis.

• DOI: 10.1007/978-1-0716-2221-6_19
• 发表时间: 2022
• 期刊: Methods in molecular biology
• 作者: Paula Montero Llopis;Ryan Stephansky;Xindan Wang

Intrinsically disordered protein regions are required for cell wall homeostasis in Bacillus subtilis.

• DOI: 10.1101/gad.349895.122
• 发表时间: 2022-09-01
• 期刊: GENES & DEVELOPMENT
• 影响因子: 10.5
• 作者: Brunet, Yannick R. R.;Habib, Cameron;Brogan, Anna P. P.;Artzi, Lior;Rudner, David Z. Z.
• 通讯作者: Rudner, David Z. Z.

XerD unloads bacterial SMC complexes at the replication terminus.

• DOI: 10.1016/j.molcel.2020.12.027
• 发表时间: 2021-02-18
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Karaboja X;Ren Z;Brandão HB;Paul P;Rudner DZ;Wang X
• 通讯作者: Wang X

Chromosome Segregation and Peptidoglycan Remodeling Are Coordinated at a Highly Stabilized Septal Pore to Maintain Bacterial Spore Development.

• DOI: 10.1016/j.devcel.2020.12.006
• 发表时间: 2021-01-11
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Mohamed AMT;Chan H;Luhur J;Bauda E;Gallet B;Morlot C;Cole L;Awad M;Crawford S;Lyras D;Rudner DZ;Rodrigues CDA
• 通讯作者: Rodrigues CDA

Dormant spores sense amino acids through the B subunits of their germination receptors.

• DOI: 10.1038/s41467-021-27235-2
• 发表时间: 2021-11-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Artzi L;Alon A;Brock KP;Green AG;Tam A;Ramírez-Guadiana FH;Marks D;Kruse A;Rudner DZ
• 通讯作者: Rudner DZ